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Unraveling the Temporal Pattern of Diet-Induced Insulin Resistance in Individual Organs and Cardiac Dysfunction in c57bl/6 Mice
Abstract
Type 2 diabetes is a heterogeneous disease characterized by insulin resistance and altered glucose and lipid metabolism in multiple organs. To understand the complex series of events that occur during the development of obesity-associated diabetes, we examined the temporal pattern of changes in insulin action and glucose metabolism in individual organs during chronic high-fat feeding in C57BL/6 mice. Insulin-stimulated cardiac glucose metabolism was significantly reduced after 1.5 weeks of high-fat feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling and GLUT4 levels. Insulin resistance in skeletal muscle, adipose tissue, and liver developed in parallel after 3 weeks of high-fat feeding. Diet-induced whole-body insulin resistance was associated with increased circulating levels of resistin and leptin but unaltered adiponectin levels. High-fat feeding caused insulin resistance in skeletal muscle that was associated with significantly elevated intramuscular fat content. In contrast, diet-induced hepatic insulin resistance developed before a marked increase in intrahepatic triglyceride levels. Cardiac function gradually declined over the course of high-fat feeding, and after 20 weeks of high-fat diet, cardiac dysfunction was associated with mild hyperglycemia, hyperleptinemia, and reduced circulating adiponectin levels. Our findings demonstrate that cardiac insulin resistance is an early adaptive event in response to obesity and develops before changes in whole-body glucose homeostasis. This suggests that obesity-associated defects in cardiac function may not be due to insulin resistance per se but may be attributable to chronic alteration in cardiac glucose and lipid metabolism and circulating adipokines.
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“In contrast, high-fat feeding that is associated with the development of insulin resistance and obesity is associated with development of LV dysfunction in many (269, 273, 296) but not all studies (40).”
From Cardiac remodeling in obesity (2008) · cites this paper as [273]
In the citing paper
“Thus C57BL6 mice when placed on a high-fat diet develop LV dysfunction as evidenced by reduced fractional shortening only after 20 wk of high-fat feeding (273).”
From Cardiac remodeling in obesity (2008) · cites this paper as [273]
In the citing paper
“This was addressed by Kim’s group via a high-fat feeding regimen in mice (273). They found that obesity-associated defects in cardiac function did not develop in concert with insulin resistance and concluded that changes in circulating adipokines could be an important contributing factor in cardiac dysfunction.”
From Cardiac remodeling in obesity (2008) · cites this paper as [273]
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“ing only after 20 wk of high-fat feeding (273).”
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Metadata
- Authors
- Park, S.-Y., Cho, Y.-R., Kim, H.-J., Higashimori, T., Danton, C., Lee, M.-K., Dey, A., Rothermel, B., Kim, Y.-B., Kalinowski, A., Russell, K. S., & Kim, J. K.
- Affiliations
- Yale University (US)
- The University of Texas Southwestern Medical Center (US)
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-12-01
- Volume
- 54
- Issue
- 12
- Pages
- 3530-3540
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2144568374
- Cited by
- 286
- References
- 58
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 14 · 2020: 14 · 2019: 11 · 2018: 8 · 2017: 16 · 2016: 17 · 2015: 24 · 2014: 21 · 2013: 29 · 2012: 20
- FWCI
- 9.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Robert E. Leet and Clara Guthrie Patterson Trust
- American Heart Association
- National Institutes of Health (5r01hl072016-10)
- U.S. Public Health Service
- National Heart, Lung, and Blood Institute (R01 HL-072016)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, U24DK59635, U24DK059635, U24-DK59635-P, P30DK045735)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- insulin resistance, cardiac insulin resistance, high-fat diet, obesity, type 2 diabetes, cardiac glucose metabolism, Akt signaling, GLUT4, skeletal muscle insulin resistance, hepatic insulin resistance, adipose tissue insulin resistance, resistin, leptin, adiponectin, intramuscular fat, intrahepatic triglyceride, cardiac dysfunction, C57BL/6 mice
- MeSH terms
- Adipose Tissue, Animals, Animal Feed, Blood Glucose, Dietary Fats, Glucose, Heart, Heart Diseases, Insulin, Insulin Resistance, Mice, Inbred C57BL, Myocardium, Organ Specificity, Glucose Clamp Technique, Mice
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